Articles

The genes that build our brains — and may drive neuropsychiatric diseases

December 17, 2018

A new study on the developing human brain sheds light on how genes switch on and off as our brains grow — and where neurological diseases may arise.

One of the most complicated parts of your body — your brain — takes decades to come into its own. Human brain development begins before we are born and continues well into late teenage years and even early adulthood.

Understanding this long and complex process is no easy feat. In a newly published study, which was itself several years in the making, researchers have now profiled how all our genes turn on and off in the human brain as it develops, from mere weeks after conception through to adulthood, and how some of these genes could play very early roles in the genesis of several major psychiatric and neurological diseases.

The study, led by researchers at Yale University, the Allen Institute and the University of Southern California and published last week in the journal Science, looked at tissue from 60 different postmortem brains, ranging in age from early in the prenatal period to a 64-year-old adult. The work came about in part through the BrainSpan consortium, a collaborative effort funded by the National Institutes of Health to map genes in the developing human brain.

The research team looked at the activity patterns of all our approximately 20,000 genes in these brain samples, either cell by cell, or across 16 different regions of the brain to map how gene activity tracks with human brain development.

They then homed in on the suite of genes that are thought to be linked to a variety of neurologial or psychiatric disorders — among them autism spectrum disorder, schizophrenia, Alzheimer’s disease, ADHD and bipolar disorder — to better understand where and when these disorders may arise.

Knowing more about the very early stages of brain disease helps focus where researchers should look for therapeutic options for a given disorder, said Ed Lein, Ph.D., Investigator at the Allen Institute for Brain Science, a division of the Allen Institute, and one of the lead authors on the study.

“The idea is we’re looking for the locus of disease in space and in time,” Lein said. “These results could help researchers who are studying these disorders know where to focus their attention.”

Not surprisingly, many of the genes associated with neuropsychiatric disorders are most active in the developing brain, in some cases even before birth. That squares with what researchers already believed about many of these disorders: that they are triggered by something going awry in the brain very early in development.

The research team then looked at postmortem brains from adults with schizophrenia, bipolar disorder or autism. The genes that seem to make these brains different from their neurotypical counterparts are not the same set of disease-linked genes that change early in development. This finding points to the importance of studying neurodevelopmental disorders where they start, not to the end result of disease, said Nenad Sestan, M.D., Ph.D., a neuroscientist at the Yale School of Medicine and one of the study’s lead authors.

“This suggests there’s a decoupling between the primary genetic cause of disease and second order effects that manifest months and years after disease begins,” Sestan said.

Brain variation

Looking across the human genome, the researchers also interesting patterns of general gene activity changes during development. Long before birth, gene activity is very different across different regions and cell types of the brain. But before we are born and during infancy and early childhood, those differences seem to fade, with different regions of the brain looking more or less the same in terms of their gene patterns. The differences pick back up again later in childhood.

It’s not clear why our brains exhibit this overarching pattern, from large differences across regions to similarities and back again.

“We don’t know whether these changes we see across development are due to new kinds of cells arising, or if a particular kind of cell is there and things are happening in that cell that make it look different over time,” said Jeremy Miller, Ph.D., a computational neuroscientist at the Allen Institute for Brain Science who worked on the BrainSpan project. More detailed studies at the single cell level would address that question, Miller said.

The data resulting from the BrainSpan project is all publicly available for other researchers to mine and analyze. The collaboration produced something that was greater than the sum of its parts, said Susan Sunkin, Ph.D., a program manager at the Allen Institute for Brain Science and an author on the study.

“We each had our own strengths, and together we were able to produce this large, publicly available dataset,” Sunkin said. “It’s nice to see that come to fruition.”